Harris Julie A, Iguchi Fukuichiro, Seidl Armin H, Lurie Diana I, Rubel Edwin W
Department of Otolaryngology, Head and Neck Surgery, Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, Washington 98195, USA.
J Neurosci. 2008 Oct 22;28(43):10990-1002. doi: 10.1523/JNEUROSCI.2697-08.2008.
The mechanisms underlying enhanced plasticity of synaptic connections and susceptibilities to manipulations of afferent activity in developing sensory systems are not well understood. One example is the rapid and dramatic neuron death that occurs after removal of afferent input to the cochlear nucleus (CN) of young mammals and birds. The molecular basis of this critical period of neuronal vulnerability and the transition to survival independent of afferent input remains to be defined. Here we used microarray analyses, real-time reverse transcription PCR, and immunohistochemistry of the mouse CN to show that deafferentation results in strikingly different sets of regulated genes in vulnerable [postnatal day (P)7] and invulnerable (P21) CN. An unexpectedly large set of immune-related genes was induced by afferent deprivation after the critical period, which corresponded with glial proliferation over the same time frame. Apoptotic gene expression was not highly regulated in the vulnerable CN after afferent deprivation but, surprisingly, did increase after deafferentation at P21, when all neurons ultimately survive. Pharmacological activity blockade in the eighth nerve mimicked afferent deprivation for only a subset of the afferent deprivation regulated genes, indicating the presence of an additional factor not dependent on action potential-mediated signaling that is also responsible for transcriptional changes. Overall, our results suggest that the cell death machinery during this critical period is mainly constitutive, whereas after the critical period neuronal survival could be actively promoted by both constitutive and induced gene expression.
发育中的感觉系统中，突触连接可塑性增强以及对传入活动操纵易感性的潜在机制尚未完全明确。一个例子是，幼年哺乳动物和鸟类的耳蜗核（CN）去除传入输入后会发生快速且显著的神经元死亡。这个神经元易损关键期的分子基础以及向不依赖传入输入的存活状态的转变仍有待确定。在此，我们利用微阵列分析、实时逆转录PCR以及对小鼠CN进行免疫组织化学分析，以表明去传入神经支配在易损的[出生后第（P）7天]和不易损的（P21）CN中导致了截然不同的一组受调控基因。关键期后，传入神经剥夺诱导了大量意想不到的免疫相关基因，这与同一时间框架内的胶质细胞增殖相对应。传入神经剥夺后，易损CN中的凋亡基因表达并未受到高度调控，但令人惊讶的是，在P21去传入神经支配后确实增加了，此时所有神经元最终都存活了。第八神经的药理活性阻断仅模拟了传入神经剥夺所调控基因中的一部分，这表明存在一个不依赖动作电位介导信号传导的额外因素，它也负责转录变化。总体而言，我们的结果表明，在此关键期内的细胞死亡机制主要是组成性的，而在关键期后，神经元存活可能由组成性和诱导性基因表达共同积极促进。
